G-protein coupled receptors play important roles in diverse signaling processes, including those involved with sensory and hormonal signal transduction. Eating disorders, which represent a major health concern throughout the world, have been linked to GPCR regulation. On the one hand, disorders such as obesity, the excess deposition of fat in the subcutaneous tissues, manifest themselves by an increase in body weight. Individuals who are obese often have, or are susceptible to, medical abnormalities including respiratory difficulties, cardiovascular disease, diabetes and hypertension. On the other hand, disorders like cachexia, the general lack of nutrition and wasting associated with chronic disease and/or emotional disturbance, are associated with a decrease in body weight.
The neuropeptide melanin-concentrating hormone (MCH), a cyclic hypothalamic peptide involved in the regulation of several functions in the brain, has previously been found to be a major regulator of feeding behavior and energy homeostasis (Qu et al. (1996) Nature 380:243–247; Rossi et al. (1997) Endocrinology 138:351–355; Shimada et al. (1998) Nature 396:670–674). It has previously been determined that MCH is the natural ligand for the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). Subsequent to this determination, SLC-1, which is sequentially homologous to the somatostatin receptors, is frequently referred to as melanin-concentrating hormone receptor (MCH receptor, MCHR or MCHR1) (see Chambers et al. (1999) Nature 400:261–265; Saito et al. (1999) Nature 400:265–269; and Saito et al. (2000) Trends Endocrinol. Metab. 11(8):299–303).
MCHR1 has been shown to couple with Gi, Go and Gq proteins (Saito et al. (2000) Trends Endocrinol. Metab. 11(8):299–303; Hawes et al. (2000) Endocrinology 141:4524–4532). Moreover, analysis of the tissue localization of MCHR1 indicates that it is expressed in those regions of the brain involved in olfactory leanning and reinforcement. The cumulative data suggest that modulators of MCHR1 should have an effect on neuronal regulation of food intake (see Saito et al. (1999) Nature 400:265–269).
Compelling evidence exists that MCH is involved in regulation of feeding behavior. First, intracerebral administration of MCH in rats resulted in stimulation of feeding. Next, mRNA corresponding to the MCH precursor is upregulated in the hypothalamus of genetically obese mice and of fasted animals. Finally, mice deficient in MCH are leaner and have a decreased food intake relative to normal mice.
MCH has also been reported to be involved in the regulation or modulation of other physiological processes, including regulation of the hypothalamus-pituitary-adrenal axis (Jezova et al. (1992) Endocrinology 130:1024–1029), modulation of water and electrolyte fluxes in the gastrointestinal tract (Hervieu et al. (1996) Endocrinology 137:561–571), stimulation of oxytocin secretion (Parkes et al. (1993) in Melanotropic Peptides, eds. Eberle, A. & Vaudry, H., New York Academy of Sciences, NY, pp. 558), regulation of sensory processing (Miller et al. (1993) Peptides 14:431–440) and modulation of the activity of monoaminergic systems (Gonzalez et al. (1997) Peptides 18:387–392).
MCH is believed to exert its activity by binding to an MCH receptor, resulting in the mobilization of intracellular calcium and a concomitant reduction in cAMP levels (see Chambers et al. (1999) Nature 400:261–265 and Shimada et al. (1998) Nature 396:670–674). MCH also activates inwardly rectifying potassium channels (Bachner et al. (1999) FEBS Lett. 457(3):522–524).
Recently, an additional GPCR for MCH, designated MCHR2 (also known as MCH-2R, MCH2, MCH2, SLT) has been identified (An et al. (2001) Proc. Natl. Acad. Sci. 98:7576–7581, Sailer et al. (2001) Proc. Natl. Acad. Sci. 98:7564–7569, Hill et al. (2001) J. Biol. Chem. 276(23):20125–20129, Wang et al. (2001) J. Biol. Chem. 276(37):34664–34670, Mori et al. (2001) Biochem. Biophys. Res. Commun. 283:1013–1018, Rodriguez et al. (2001) Mol. Pharmacol. 60(4):632–639). Protein sequence analysis indicates that MCHR2 has only 36% overall homology to MCHR1, but analysis of the tissue localization of MCHR2 indicates that its expression pattern is similar to that of MCHR1. Both receptors are expressed in regions of the brain, including the hypothalamus, and MCHR2 has been detected in other tissues that have been reported to express MCHR1, including adipose tissue and pituitary. In contrast to MCHR1, MCHR2 has been shown to couple primarily to Gq protein.
While the similar expression patterns suggest that both MCHR1 and MCHR2 are important in processes regulated by MCH, such as regulation of feeding behavior and energy homeostasis, the differences in G protein coupling suggest that MCHR2 may have a role in diverse processes, such as fluid balance, behavioral responses, learning and processes regulated by ligands other than MCH.
The discovery of small molecules that modulate the function of MCHR2 is useful for the study of physiological processes mediated by MCHR2 and the development of therapeutic agents to treat conditions and disorders associated with processes mediated by MCHR2. In this application we describe novel compounds which display such desirable activity.